By - April 05, 2022
Blood transfusions support victims of trauma and their histories are intertwined. In response to WWI, Rous and Turner introduced an anti-coagulant and glucose solution to safely store whole blood. With further refinement, J.F. Loutit and Patrick L. Mollison created the acid citrate dextrose solution in 1943. Many refinements to blood and plasma processing were discovered during the period after the first world war and surrounding the second world war.
The 1940s were a time of great discovery in the history of blood banking.1 Dr. Edwin Cohn published the process of Cohn fractionation for extracting albumin from plasma.2,3,4 At that same time, Dr. Charles Drew was organizing the first coordinated system to provide blood products to patients.5 Dr. Drew, widely recognized as the “Father of Blood Banking,” honed the processes of collecting blood donations, processing those donations and making available on a large-scale donated blood therapies for patients. He was appointed as the first director of the American Red Cross National Blood Donor Service.6 These early pioneers paved the way for incredible discoveries, further refinements, and laid the foundation for the specialty of blood banking/transfusion medicine.
A derivative of fresh frozen plasma (FFP), cryopreciptated antihemophilic factor (Cryo), was discovered to contain factor VIII (FVIII) by Dr. Judith Graham Pool in 1964.7 Whereas the volume of fresh frozen plasma was too large to effectively provide enough FVIII for the effective treatment of hemophilia, Dr. Pool discovered that the slow thaw of FFP generated a precipitated paste that was abundant in the deficient clotting factor. This last-to-thaw property was a simplified fractionation process that could be broadly used by community blood banks. Dr. Pool’s steadfast research and commitment provided a critical advancement in the availability of plasma for patient care. Modern blood banks largely supply the same four blood fractions today that were originally identified during this age of discovery: red cells, platelets, plasma, and cryoprecipitated antihemophilic factor.
Modern plasma fractionation remains largely based on the original Cohn process, but advances in technology have led to a myriad of highly specified applications. Today, plasma fractions that originate from the pooling of tens of thousands of individual donations can be reduced and refined to produce specific immunoglobulin class pharmaceuticals such as cytomegalovirus or hepatitis B immune globulin and specific proteins such as a-1 antitrypsin, fibrin, prothrombin, antithrombin, and specific clotting factors. Because of the human origin of the starting material and the pooling of 10,000 to 50,000 donations required for industrial processing, the major risks associated with plasma fractionation are the transmission of blood-borne infectious agents—a one-transfers-too-many scenario if an infectious pathogen were to survive pathogen inactivation methods. Many new pathogens have been discovered in part due to the practices and therapeutic value of blood. In 2020, Dr. Harvey J. Alter was awarded the Nobel Prize in Medicine for discovering hepatitis C virus and dedicating a lifetime to safer blood transfusion practices. The research discoveries of these pioneers has led to targeted innovation in pathogen inactivation. A complete set of pathogen inactivation interventions and, most particularly, the use of dedicated viral inactivation and removal treatments, is now standard procedure throughout the production chain of fractionated plasma products over the last twenty years. In order to ensure optimal safety, modern blood fractions are treated to inactivate HIV, hepatitis B virus, and hepatitis C virus and a host of other potentially known and unknown pathogens.8
Convalescent plasma (CP) is a term used to describe the transfer of protective antibodies from a person who has recovered from a disease into a patient who is acutely suffering from the same disease. In other words, convalescent plasma provides passive immunization to a patient before their own body has had time to build active immunity. Convalescent plasma has a long and storied transfusion history that is interwoven with the history of epidemics and global pandemics.9 Although CP is generally thought to have had its first use during the Spanish influenza pandemic, the utilization of prophylactic and therapeutic CP began at the turn of the 19th century.
Once termed “serotherapy,” convalescent plasma has been used to treat patients with polio, measles, and mumps, among many other surprising conditions. CP is probably best known for its use during the Spanish influenza pandemic of 1918-1920, where it is purported to have had a limited efficacy.10 More recently, CP was utilized to curb the effects of both the Ebola virus outbreak of 2014-2016 and the COVID-19 pandemic.11 The past 10 years has reaffirmed the ongoing importance of plasma transfusion in the therapeutic arsenal of the management of rapidly emerging epidemics and pandemics. Nevertheless, the overall efficacy and specific role of CP remains to be more clearly understood. When CP was used to treat acute Ebola virus disease patients, the results of showed a trend in survival that unfortunately was not significant. More recently, CP was widely used in the United States under multiple research protocols to treat COVID-19. The efficacy of CP in the setting of COVID-19 infection likewise remains unclear. The evidence is accumulating to suggest that CP might not be as useful in either the early stages or later stages of acute SARS CoV-2 viral infections.12,13 Nevertheless, the utility of CP therapy as a treatment option for any acute infection will likely remain a viable option if the history of CP utilization provides a window into the future of CP research.
In the course of the past 100 years, blood transfusion has grown from a basic concept to a medical subspecialty within the practice of pathology. Blood has been investigated, separated, fractionated, purified, and replicated using recombinant protein technologies. Novel pathogens emerged in the blood supply, were identified and then inactivated. Blood transfusions remain a cornerstone of therapy for many patients: acute trauma, cancer therapy, cellular therapy and convalescent plasma therapy. Thank you to the transfusion medicine pioneers of the past, present, and future for ever improving the safety, purity and potency of the gift of life. The next 100 years of blood transfusion medicine looks even more promising as transfusion medicine research and discovery is just beginning.
The blood program in world war II. Kendrick DB, Coates JB (EIC). The historical unit: United States Army Medical Service: 1964:p 14.
Cohn EJ, Oncley JL, Strong LE, Hughes WL, Armstrong SH. Chemical, clinical, and immunological studies on the products of human plasma fractionation. I. The characterization of the protein fractions of human plasma. J Clin Invest. 1944 Jul; 23(4): 417–432.
Cohn EJ, Strong EL, Hughes WL, Mulford DJ, Ashworth JN, Melyn M, Taylor HL. Preparation and properties of serum and plasma proteins A system for the separation into fractions of the protein and lipoprotein components of biological tissues and fluids. J Am Chem Soc. 1946;72:459–475.
Starr D. Dr. Edwin Cohn, The ‘King of Blood’. Smithsonian. 1995 March;25(12),124-38.
Bull DC, Drew CR. The preservation of blood. Ann Surg. 1940 Oct;112(4):498-501.
Tan SY, Merritt C. Charles Richard Drew (1904-1950): Father of blood banking. Singapore Med J. 2017 Oct;58(10):593-594.
Kasper CK. Judith Graham Pool and the discovery of cryoprecipitate. Haemophilia 2012, 18, 833–35.
Burnouf T. Modern plasma fractionation. Transfus Med Rev. 2007 Apr; 21(2): 101–117.
Mock J. The peculiar 100-plus-year history of convalescent plasma. Smithsonian: Special Report. 2020 Sep 1.
Marson P, Cozza A, De Silvestro G. The true historical origin of convalescent plasma therapy. Transfus Apher Sci. 2020 Oct;59(5).
van Griensven J, Edwards T, de Lamballerie X, Semple MG, Gallian P, Baize S, Horby PW, Raoul H, Magassouba N, Antierens A, Lomas C, Faye O, Sall AA, Fransen K, Buyze J, Ravinetto R, Tiberghien P, Claeys Y, De Crop M, Lynen L, Bah EI, Smith PG, Delamou A, De Weggheleire A, Haba N. for the Ebola-Tx Consortium. Evaluation of Convalescent Plasma for Ebola Virus Disease in Guinea N Engl J Med. 2016 Jan 7; 374(1): 33–42.
Bégin P, Callum J, Jamula E, Cook R, Heddle NM, Tinmouth A, Zeller MP, Beaudoin-Bussières G, Amorim L, Bazin R, Loftsgard KC, Carl R, Chassé M, Cushing MM, Daneman N, Devine DV, Dumaresq J, Fergusson DA, Gabe C, Glesby MJ, Li N, Liu Y, McGeer A, Robitaille N, Sachais BS, Scales DC, Schwartz L, Shehata N, Turgeon AF, Wood H, Zarychanski R, Finzi A; CONCOR-1 Study Group, Arnold DM. Convalescent plasma for hospitalized patients with COVID-19: an open-label, randomized controlled trial. Nat Med. 2021 Sep 9. doi: 10.1038/s41591-021-01488-2. Online ahead of print.
Korley FK, Durkalski-Mauldin V, Yeatts SD, et al. Early convalescent plasma for high-risk outpatients with Covid-19. NEJM 2021; 385:1951-60.
Professor and Vice Chair of Pathology